Phagocyte NADPH oxidase restrains the inflammasome in ANCA-induced GN.
J Am Soc Nephrol
; 26(2): 411-24, 2015 Feb.
Article
en En
| MEDLINE
| ID: mdl-25012177
ABSTRACT
ANCA-activated phagocytes cause vasculitis and necrotizing crescentic GN (NCGN). ANCA-induced phagocyte NADPH oxidase (Phox) may contribute by generating tissue-damaging reactive oxygen species. We tested an alternative hypothesis, in which Phox restrains inflammation by downregulating caspase-1, thereby reducing IL-1ß generation and limiting NCGN. In an antimyeloperoxidase (anti-MPO) antibody-mediated disease model, mice transplanted with either gp91(phox)-deficient or p47(phox)-deficient bone marrow showed accelerated disease with increased crescents, necrosis, glomerular monocytes, and renal IL-1ß levels compared with mice transplanted with wild-type bone marrow. IL-1ß receptor blockade abrogated aggravated NCGN in gp91(phox)-deficient mice. In vitro, challenge with anti-MPO antibody strongly enhanced caspase-1 activity and IL-1ß generation in gp91(phox)-deficient and p47(phox)-deficient monocytes compared with wild-type monocytes. This enhanced IL-1ß generation was abrogated when caspase-1 was blocked. ANCA-induced superoxide and IL-1ß generation were inversely related in human monocytes. Furthermore, transplantation of gp91(phox)/caspase-1 double-deficient bone marrow rescued the accelerated NCGN phenotype in gp91(phox) bone marrow-deficient mice. These results suggest that Phox-generated reactive oxygen species downregulate caspase-1, thereby keeping the inflammasome in check and limiting ANCA-induced inflammation. IL-1 receptor blockade may provide a promising strategy in NCGN, whereas our data question the benefit of antioxidants.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Fagocitos
/
NADPH Oxidasas
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Anticuerpos Anticitoplasma de Neutrófilos
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Inflamasomas
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Glomerulonefritis
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Año:
2015
Tipo del documento:
Article